Management of Hypoparathyroidism: Present and Future

SPECIAL FEATURE

Position Statement

John P. Bilezikian1, Maria Luisa Brandi2, Natalie E. Cusano1, Michael Mannstadt3, Lars Rejnmark4, René Rizzoli5, Mishaela R. Rubin1, Karen K. Winer6, Uri A. Liberman7, and John T. Potts, Jr3

1Columbia University College of Physicians & Surgeons, NY, NY, United States; 2Department of Surgery and Translational Medicine, University of Florence, Italy; 3Massachusetts General Hospital, Boston, MA, United States; 4Aarhus University Hospital, Aarhus, Denmark; 5Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; 6Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States; 7Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Context: Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism.

Evidence acquisition: Contributing authors reviewed the literature regarding physiology, pathophysiology and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized.

Evidence synthesis: Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence of PTH, the gastrointestinal tract, kidneys, and skeleton are all affected leading to hypocalcemia, hyperphosphatemia, reduced bone remodeling, and an inability to conserve filtered calcium. Acute hypocalcemia can be a medical emergency presenting with neuromuscular irrita- bility. The recent availability of human recombinant PTH(1–84) has given hope that management of hypoparathyroidism with the missing hormone in this disorder will provide better control and reduced needs for calcium and vitamin D.

Conclusions: Hypoparathyroidism is associated with abnormal calcium and skeletal homeostasis. Control with calcium and active vitamin D can be a challenge. The availability of PTH(1–84) replacement therapy may usher new opportunities for better control with reduced supplementation requirements.

Physiology, pathophysiology and nutritional aspects of hypoparathyroidism

o protect the organism against overload or deficiency tration as stable as possible, because of the high sensitivity T of calcium, phosphate and other ions, homeostasis is of a variety of cell systems or organs, including the central aimed at maintaining extracellular concentrations as con- nervous system (CNS), muscle, and exo-/endocrine stant and minimally variant as possible (1). It is particu- glands, to small variations in this divalent cation. Extra- larly important to maintain extracellular calcium concen- cellular calcium is maintained within a narrow range by

doi: 10.1210/jc.2015-3910 J Clin Endocrinol Metab press.endocrine.org/journal/jcem 1

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. 2 Management of Hypoparathyroidism J Clin Endocrinol Metab bidirectional calcium fluxes taking place at the level of the ing the large intestine is complexed to various anions and intestine, bone and kidney. In the absence of parathyroid is thereby poorly bioavailable. hormone or in states of resistance to its action, however, When hypocalcemia occurs and its etiology is not extracellular calcium concentration is much more likely to known, magnesium deficiency should be suspected (12). fall since homeostatic mechanisms in all three target or- Magnesium deficiency is associated with impaired secre- gans are impaired. tion and action of PTH. Magnesium is present in all nutrients from cellular origin. Dietary sources of magnesium Intestinal calcium absorption include almonds, soybean, seeds, wheat germ, wheat bran, Under normal conditions, intestinal absorption of cal- millet, dark green vegetables, fruit, and seafood. Recom- cium represents approximately 20%-30% of ingested cal- mended daily allowance of magnesium is 420 and 320 cium (2, 3). The latter could be decreased in pathological mg/d for men and women, respectively. Dietary inade- conditions such as celiac disease, in which net calcium quacy of magnesium is most unusual under normal cir- absorption is reduced. Except in the elderly with achlo- cumstances. But if magnesium is being persistently lost rhydria, in whom calcium carbonate absorption may be from the intestine or kidney, dietary intake may become impaired (4), the different forms of calcium including insufficient. Net intestinal absorption of magnesium is dairy products are similarly absorbed (5). Dairy products proportional to intake, but usually averages 35 to 40%. are an important dietary source of calcium because of their Phosphate and cellulose phosphate form a complex with high calcium content and absorbability (6). They provide magnesium, thereby impairing its absorption. A low pH is more calcium, protein, magnesium, potassium, zinc and important to displace magnesium bound to dietary fibers phosphorus per calorie than any other usual food found in and to make it available to absorptive processes. Thus, the adult diet (7). Furthermore, dairy products are rich in prolonged nasogastric suction or chronic diarrhea, par- aromatic amino acids, which stimulate hepatic production ticularly when due to laxative abuse, are risk factors for of IGF-1 (8). Intestinal absorption of calcium is enhanced magnesium depletion. Upper gastrointestinal (GI) tract by IGF-1 by virtue of its effect to stimulate renal calcitriol. fluid contains 2 mmol/L of magnesium whereas in diar- When ingested during a protein-containing meal, calcium rheal fluid magnesium concentration may be as high as 30 is better absorbed with less variability (9). Recommended mmol/L. dietary allowance for protein is 0.8 g/kg body weight. However, in older people, it appears that higher intakes Role of the kidney are necessary, approximately 1.1–1.2 g/kg body weight. PTH increases renal tubular calcium reabsorption. In Intestinal calcium absorptive capacity is mainly con- chronic hypoparathyroidism, relative renal calcium clear- trolled by calcitriol, which stimulates calcium transport ance is higher than normal despite reduced glomerular through both genomic and nongenomic mechanisms (2). filtration of calcium. There is some correlation between The normal daily production rate of calcitriol is 0.5–1 the renal clearances of calcium and sodium. High sodium mcg/d (10). In hypoparathyroidism, the lack of PTH is intakes may be associated with hypercalciuria. A sound associated with lower calcitriol levels, hence reduced in- measure in the management of patients with hypopara- testinal absorption of calcium. The hyperphosphatemia of thyroidism is to limit sodium intake, a step that may re- hypoparathyroidism also limits the production of cal- duce hypercalciuria. Loop diuretics increase urinary calcitriol. Under these conditions, plasma calcium homeo- cium excretion and are contraindicated in patients with stasis is dependent on higher intestinal cation influx. In- hypoparathyroidism. creasing dietary intake of calcium, calcium supplements and active vitamin D metabolites can all facilitate calcium Role of bone resorption absorption. To avoid substantial increases in postprandial About 1% of total bone calcium exchanges every urinary calcium excretion, calcium intake should be month, through bidirectional fluxes, under the influence evenly distributed during the day. In many instances, in- of parathyroid hormone and/or calcitriol. Besides calcitri- creasing the amount of calcitriol can reduce the amount of ol’s main action to enhance dietary calcium absorption, an supplemental calcium required. additional effect is to stimulate bone resorption, shown Prebiotics such as galacto-oligosaccharides are fer- best in animal models (13). In the absence of parathyroid mented by microflora in the large intestine, lowering pH hormone, calcium efflux from bone is more dependent and thereby enhancing calcium absorption (11). The large upon calcitriol. A large variety of substances either circu- intestine contains a potent vitamin D-dependent calcium lating or produced locally, or present in the bone matrix, transport system, which under normal conditions, con- are also capable of influencing these fluxes (1), but they are tributes little to calcium homeostasis, since calcium reach- not available pharmacologically. Many nutrients have

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. doi: 10.1210/jc.2015-3910 press.endocrine.org/journal/jcem 3 been shown, primarily in animal studies, to influence bone fallen dramatically at the time they present with symp- resorption, such as dried plum, blueberries, fish oil, zinc, toms. Finally, there are some women who typically be- grapes and the phyto-estrogen genistein (14–19). How- come symptomatic during the luteal phase of their men- ever, these nutrients appear to reduce bone turnover, in- strual cycle. In these situations, clinical judgment and stead of stimulating bone resorption, and cannot therefore prompt decision making to opt for IV calcium are be considered useful as therapeutic adjuncts in required. hypoparathyroidism. When clinical circumstances dictate urgent treatment, IV Ca2ϩ salts are used. The goals of IV calcium therapy are Management of acute hypocalcemia to control symptoms, reverse signs (eg, prolonged QT in- In hypoparathyroidism, hypocalcemia can occur terval), and to restore the serum calcium level to the lower acutely and become a true medical emergency. Hypocal- end of the normal range. Initially, IV calcium (1 to2gof ϩ cemia is defined as an ionized serum calcium (Ca2 ) con- calcium gluconate, equivalent to 90–180 mg elemental centration that falls below the lower limit of the normal calcium, in 50 mL of 5% dextrose) can be infused over 10 range. Approximately 50% of the total serum Ca is in the to 20 minutes. As is true for the IV administration of any ionized fraction, with the remainder being protein-bound electrolyte solution, calcium should not be given more rap- (predominantly to albumin) or complexed to anions such idly because of the serious risk of cardiac dysfunction, as phosphate. Estimation of the corrected serum total Ca including systolic arrest. This dose of calcium gluconate can be obtained with the following formula: corrected will typically increase the serum Ca2ϩ concentration for serum total Ca ϭ measured total Ca ϩ [0.8 x (4.0-mea- only several hours. Therefore, the acute IV administration sured serum albumin)]. In assessing the degree of hypocal- of calcium gluconate should be followed by a slower in- cemia, the corrected serum calcium should be used. In fusion of calcium. settings where an accurate, direct ionized serum calcium Ten percent calcium gluconate (90 mg of elemental cal- can be obtained, this measurement can also be useful in cium per 10 mL) is used. Calcium gluconate is preferred guiding the acute therapeutic approach. Several recent re- because it is less likely than calcium chloride to cause tissue views present detailed information on this topic (20–24). necrosis if extravasated into the contiguous subcutaneous The treatment of hypocalcemia in hypoparathyroidism space. An IV solution containing 1 mg/mL of elemental is influenced not only by the actual calcium concentration calcium is prepared by adding 11 g of calcium gluconate but also by any associated symptoms. In hypoparathy- (equivalent to 990 mg elemental calcium) to normal saline roidism, many subjects chronically demonstrate calcium or 5% dextrose water to provide a final volume of 1000 levels in the low normal or mild hypocalcemic range. The mL. The calcium should be diluted in dextrose and water symptoms of hypocalcemia do not always follow strictly or saline because concentrated calcium solutions are irri- the extent to which the calcium is low. The severity of tating to veins. The IV solution should not contain bicar- symptoms (paresthesias, carpal- pedal spasm, broncho- or bonate or phosphate, either one of which can form insol- laryngospasm, tetany, seizures or mental status changes) uble calcium salts. The solution is administered at an and signs (Chvostek’s or Trousseau’s signs, bradycardia, initial infusion rate of 50–100 mL/hr (equivalent to 50 impaired cardiac contractility and prolongation of the QT –100 mg/hr). The dose can be adjusted to maintain the interval) all depends upon the absolute level of calcium, corrected serum calcium concentration at the lower end of the rate of decrease, and individual variability. No two the normal range. A typical infusion rate is 0.5 to 1.5 subjects appear to be alike in these respects. Some patients mg/kg of elemental calcium per hour. Over 8–10 hours, with marked hypocalcemia will appear to be asymptom- this infusion protocol will deliver as much as 15 mg/kg atic while others with what appears to be mild hypocal- body weight, raising the serum calcium levels by approx- cemia may be symptomatic. imately 2 mg/dL (0.5 mmol/l). The electrocardiogram Clinical features of hypocalcemia for which intrave- (ECG) can be monitored if it is warranted by the situation, nous (IV) calcium administration should be considered are such as in the setting of digoxin therapy. indicated above. In addition, even though some patients Active vitamin D metabolites can be additionally ad- with marked hypocalcemia [ie, corrected calcium Յ 7.0 ministered. Because PTH is an important facilitator of the mg/dL (Ͻ1.75 mmol/L)] may not be symptomatic, IV ther- renal conversion of 25-hydroxyvitmain D to 1,25-dihy- apy may be indicated because at those levels, life-threat- droxyvitamin D (calcitriol), this active form of vitamin D ening features can appear rather suddenly such as laryn- is preferred for treatment of patients with hypoparathy- geal spasm and seizures. Patients who become unable to roidism. The initial dose of calcitriol is typically 0.25 to 0.5 take or absorb oral supplements can become quickly ␮g twice daily. Its rapid onset of action (hours) and bio- symptomatic even though the serum calcium may not have logic half-life of 4–6 hours make it a useful adjunct in the

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. 4 Management of Hypoparathyroidism J Clin Endocrinol Metab management of acute hypocalcemia. Moreover, the cal- data available on the use of PTH (1–34) or PTH (1–84) in cemic response to calcitriol can persist for more than 24 the more common setting of acute hypocalcemia against a hours after a single oral dose (25). backdrop of chronic hypoparathyroidism. In patients who present with symptomatic hypocalce- In summary, because a normal level of ionized calcium mia requiring urgent IV calcium replacement therapy, the is critical for many vital cellular functions, acute hypocal- possible coexistence of hypomagnesemia should always cemia in patients with hypoparathyroidism can be a life- be considered. This is particularly true in patients who are threatening emergency. Urgent management should be not known to have hypoparathyroidism. Their acute hy- guided by the level of serum calcium, and most impor- pocalcemia could be explained by the reversible hypo- tantly, by the nature and severity of the symptoms. With parathyroidism of hypomagnesemia. In this setting para- the administration of IV calcium therapy, serum calcium thyroid hormone secretion is blocked as is the activation levels can be safely increased and patients typically expe- of vitamin D. In addition, there is a reversible resistance to rience immediate and substantial relief of symptoms. PTH that is evident when magnesium is administered and circulating PTH rapidly rises. While IV calcium is a key Conventional therapy of hypoparathyroidism element of acute therapy, the hypocalcemia will be diffi- Standard therapy of hypoparathyroidism is oral cal- cult to correct without first normalizing the serum mag- cium and vitamin D supplementation (both active and par- nesium concentration. If the serum magnesium concen- ent forms) at varying doses, based on clinical judgment. tration is low, 2 g (16 mEq) of magnesium sulfate should The goals of therapy are to a) ameliorate symptoms of be infused as a 10% solution over 10 to 20 minutes, fol- hypocalcemia; b) maintain fasting serum calcium within lowed by1g(8mEq) in 100 mL of infusate per hour. If or slightly below to the low-normal range; c) maintain magnesium administration is too rapid, excessive urinary fasting serum phosphorus within the high normal range or losses of both magnesium and calcium can ensue. The IV only slightly elevated; d) avoid or minimize hypercalciuria; route is generally preferred, even though 90% is cleared by e) maintain a calcium-phosphate product at levels well the kidney in the setting of normal renal function. Mag- below the upper limit of normal (Ͻ55 mg2/dL2 or 4.4 nesium can be administered by the intramuscular (IM) mmol2/L2); and f) avoid ectopic calcification of the kidney route if necessary, but is generally avoided because of the (stones and nephrocalcinosis) and other soft tissues. Se- relatively high volume that is required to inject, pain, and rum calcium (corrected for albumin), phosphorus and cre- “sterile” abscesses that can form. Of note, if a hypopara- atinine concentrations should be measured weekly to thyroid patient is acutely symptomatic in the setting of monthly during dose adjustments, and twice annually hypocalcemia and hypomagnesemia (eg, with seizures), IV once a stable regimen has been reached. Urinary calcium calcium should be administered acutely prior to parenteral and creatinine should be considered during dose adjust- administration of magnesium. ments and should be measured twice annually on a stable The serum calcium level should be measured frequently regimen to evaluate for renal toxicity (21, 22). in the acute setting. The recurrence of symptoms caused by hypocalcemia may indicate the need to increase the infu- Calcium sion rate and should be correlated with a simultaneous Calcium carbonate and calcium citrate are the most serum calcium value to assess the progress of treatment. common forms of oral calcium supplementation. Calcium Intravenous calcium should be continued until the patient carbonate contains 40% elemental calcium and calcium is receiving an effective regimen of oral calcium and vita- citrate contains 21% elemental calcium. Calcium carbon- min D. Intravenous infusions are generally tapered slowly ate typically requires fewer pills per day and is less expen- (over a period of 24 to 48 hours or longer) while oral sive and therefore more cost-effective (31). Absorption of therapy is adjusted. Oral calcium and parent vitamin D calcium carbonate is best if taken with meals and with acid therapy, in addition to calcitriol, should be initiated as present in the stomach, while calcium citrate is well ab- soon as is practical. sorbed without regard to meals and does not require gas- There are limited data on the use of parathyroid hor- tric acid (32). Calcium citrate, therefore, may be more mone in human subjects who are acutely hypocalcemic. A effective in patients with achlorhydria or in the presence of few cases have been reported in patients in the postoper- proton pump inhibitors. Illustrating this point, there are ative period status post parathyroidectomy, thyroidec- case reports of hypoparathyroid patients presenting with tomy and renal transplant, and one hypoparathyroid in- tetany after initiating therapy with proton pump inhibi- dividual with hypocalcemic cardiomyopathy (26–29). tors (33–35). Calcium citrate may also be preferred over There is a single case report describing the use of PTH in calcium carbonate in those who complain of worsening acute neonatal hypocalcemia (30). There are no systematic constipation. Certain “natural” forms of calcium such as

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. doi: 10.1210/jc.2015-3910 press.endocrine.org/journal/jcem 5 dolomite may contain significant amounts of lead or other specific vitamin D analogues. While toxicity with cal- heavy metals and are not recommended (36, 37). Coral citriol is easily managed due to the short half-life, severe calcium, while touted for unsubstantiated health benefits, hypercalcemia complicated by renal failure has been de- is essentially an expensive source of calcium carbonate scribed with dihydrotachysterol therapy (48). (38). Calcium glubionate, gluconate and lactate contain Patients are also typically supplemented with parent lower amounts of elemental calcium (6.6%, 9% and 13%, vitamin D [vitamin D2 (ergocalciferol) or vitamin D3 respectively) and are generally not used for chronic sup- (cholecalciferol)]. Vitamin D3 may be more potent than plemental calcium therapy. The amorphous polymorph of D2, although this has not been firmly established (49, 50). calcium carbonate was recently stabilized and the results The half-life of the parent vitamin is 2 to 3 weeks, which of a phase I trial in healthy postmenopausal women some experts feel can help provide smoother control given showed increased fractional calcium absorption com- the short half-life of calcitriol. There is also the possibility pared to crystallized calcium carbonate (39). Results of that providing the parent vitamin D compound may lead phase I and II trials in hypoparathyroid subjects have not to heretofore unidentified vitamin D analogues that are yet been published. The amount of elemental calcium sup- beneficial with regard to “off target” effects. 25-hy- plementation required by patients with hypoparathyroid- droxyvitamin D might be able in high concentrations to ism varies greatly, typically 500–1000 mg 2–3 times daily, occupy vitamin D receptors and thereby have activity. although more frequent dosing may be necessary. Nonrenal expression of 1␣-hydroxylase, not regulated by PTH, is another potential source of 1,25-dihydroxyvita- Vitamin D metabolites min D (40). Active vitamin D (1,25-dihydroxyvitamin D; calcitriol) Hypercalcemia is of particular concern in individuals stimulates intestinal calcium transport and absorption treated with large doses of parent vitamin D (ergo- or and promotes bone remodeling (40). Since PTH stimulates cholecalciferol) which can accumulate in large amounts in the renal 1␣-hydroxylation of 25-hydroxyvitamin D, its fat stores and, when released, can result in prolonged hy- absence, as in hypoparathyroidism, is associated with im- percalcemia (51). In settings where calcitriol is not readily paired activation of vitamin D. Thus, along with calcium, available and/or is too expensive, parent vitamin D can be supplemental active vitamin D is integral to the chronic used with due regard to the cautionary note regarding management of hypoparathyroidism. Peak serum concen- vitamin D toxicity. We recommend maintaining serum trations of calcitriol are reached within 3 to 6 hours of levels of 25-hydroxyvitamin D to within the normal range. administration and the increase in serum calcium concen- In this disorder, as in other metabolic bone diseases, levels tration typically follows 1–3 days later. The elimination of Ͼ30 ng/mL (80 nmol/L) are desirable (52). half-life is 5–8 hours in adults. In hypoparathyroidism, the typical dose for calcitriol is 0.25 to 2 ␮g daily which in- Adjunctive treatments cludes the normal daily production rate of calcitriol (10, Thiazide diuretic therapy can be used to increase distal 41–44), although higher levels are sometimes necessary. renal tubular calcium reabsorption, usually in conjunction When amounts greater than 0.75 ␮g are required, cal- with a low-salt diet to promote calcium retention. Effects citriol is typically administered in divided doses. Measure- on calcium excretion can be noted within 3 to 4 days of ment of 1,25-dihydroxyvitamin D can be employed in spe- starting treatment (53, 54). The dose of hydrochlorothi- cial situations where compliance and/or absorption might azide is 25 to 100 mg daily. Due to the short plasma half- be a concern and parenteral administration of calcitriol is life of hydrochlorothiazide, twice daily dosing is most of- considered. ten needed (ie, 25–50 mg twice daily). Chlorthalidone is 1␣-hydroxyvitamin D (alfacalcidol) and dihydrot- another thiazide diuretic that can be used. Doses at the achysterol are vitamin D analogues in use for hypopara- higher end of the range are usually necessary to signifi- thyroidism outside the United States. They are rapidly ac- cantly lower urinary calcium with thiazide therapy, but tivated by the liver to 1,25-dihydroxyvitamin D3 and 25- these higher doses can be associated with hypokalemia, hydroxydihydrotachysterol, respectively. The time to hypomagnesemia and hyponatremia. Potassium supple- onset of action of alfacalcidol is similar to calcitriol at 1–3 mentation or a potassium- and magnesium-sparing di- days, with a longer offset of 5–7 days (41, 43, 45, 46). The uretic (eg, amiloride 2.5 to 5 mg twice a day) may be used time to onset of action of dihydrotachysterol is 4–7 days, in conjunction with hydrochlorothiazide to prevent hy- with a time to offset of action of 7–21 days (47, 48). The pokalemia and hypomagnesemia (21). The use of thiazide typical dose for alfacalcidol is 0.5–3.0 ␮g daily and for diuretics varies among experts with some feeling they are dihydrotachysterol 0.2–1.0 mg daily. Dihydrotachysterol very helpful while others opining that they are not partic- is used less often now due to the development of the more ularly helpful. Thiazide diuretics are not advised in con-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. 6 Management of Hypoparathyroidism J Clin Endocrinol Metab genital hypoparathyroidism due to Autoimmune Polyen- min, creatinine) should be monitored varies with the suc- docrine Syndrome type 1 (APS-1) who have concurrent cess of controlling those biochemical parameters. In very Addison’s Disease or in Autosomal Dominant Hypocal- well controlled patients, yearly or semiannual measure- cemia (ADH). In situations where a diuretic is needed for ments might be sufficient. More often, though, more fre- other reasons, such as congestive heart disease, a thiazide quent monitoring is needed such as every 3 or 6 months. diuretic should be considered, and loop diuretics should be 24-hour urinary calcium and creatinine excretion should avoided. be measured at least once yearly because hypercalciuria is Phosphate binders or low-phosphate diets are generally a common concern in this disease. Some experts also rec- not used unless hyperphosphatemia is particularly trou- ommend urinary magnesium measurement. There are sit- blesome (22). Patients with activating calcium sensor re- uations in which more frequent measurement of urinary ceptor mutations may require substantial magnesium sup- calcium and a more complete urinary profile for stone risk plementation due to urinary magnesium losses (55). A factors may be needed. At the initial evaluation, baseline small study in hypoparathyroid subjects demonstrated imaging of the kidneys with ultrasound or computed to- that magnesium supplementation does not alter plasma mography (CT) is recommended (62). Surveillance for the calcium concentrations in individuals with normal serum appearance of nephrolithiasis or nephrocalcinosis may re- magnesium (56). quire repeat ultrasound or other imaging modality every 5 years or earlier if signs or symptoms of kidney stones de- Clinical aspects of chronic management velop. Central nervous system calcifications, especially in Treatment goals for patients with chronic hypopara- the basal ganglia, are a well-known complication of hy- thyroidism are noted in the previous section (21). One of poparathyroidism (57, 63). However, the clinical signifi- the keys to management is to individualize therapy with cance of these calcifications is unclear. In patients with particular reference to the serum calcium level. The gen- long-standing hypoparathyroidism, imaging of the brain erally accepted target serum calcium concentration for for basal ganglia and other sites of ectopic calcification is these patients is in the low-normal range, a state in which reasonable. symptoms of hypocalcemia are generally uncommon. Patients suffering from hypoparathyroidism are at risk Higher serum levels of calcium, even within the normal for cataracts (64). While the standard senile cataract is range, are to be avoided, because they can increase the risk characterized by nuclear opacities, cataracts associated of complications. In addition, in some patients, enhanced with hypoparathyroidism show predominantly cortical sensitivity to the serum calcium concentration may lead to involvement. Slit-lamp and ophthalmoscopic examina- symptoms of hypercalcemia even though serum calcium is tions are recommended in all patients who develop symp- only in the high-normal range. Conversely, some patients toms such as blurred vision or sensitivity to light. Surgical whose serum calcium is in the low normal range may ex- treatment of cataracts is typically a decision made by the perience symptoms of hypocalcemia. Individualized man- ophthalmologist. agement, therefore, is necessary to optimize patient care. Children with hypoparathyroidism can have a wide va- Patients with hypoparathyroidism are at risk of many riety of dental manifestations and abnormalities such as complications, both from the disease itself as well from hypoplastic teeth that might require special care. adverse effects of conventional treatment regimens with In adults with hypoparathyroidism, bone microarchi- oral calcium and active vitamin D (57–59). It is not pos- tecture is abnormal and bone mineral density (BMD) as sible to determine with certainty whether some of the com- measured by dual-energy x-ray absorptiometry (DXA) is plications of hypoparathyroidism such as ectopic calcifi- often above age- and sex-matched controls (22). The clin- cations and kidney stones are due to the disease, to ical significance of these abnormalities is unclear. Guide- treatment with calcium and vitamin D, often requiring lines for when repeat measurements should be made very high doses, or both. should follow recommendations of the International So- There are no data from clinical trials that gives guidance ciety of Clinical Densitometry (65). to the optimal follow-up intervals or the optimal fre- A key aspect of ongoing follow-up is engaging the pa- quency of laboratory and imaging tests. As a result, guide- tient as a partner in his or her medical care. Patient orga- lines for the management of the disease have only recently nizations that have formed in many countries, as well as been offered (60, 61). This section deals only with the use rare disease organizations, offer a variety of resources for of conventional approaches to management. Replacement patients and their families, as well as health care providers therapy with rhPTH (1–84) is covered in the next section. (66–69). It is highly desirable for patients with hypopara- The frequency with which biochemical parameters (se- thyroidism to have a basic understanding of the underly- rum calcium, potassium, magnesium, phosphate, albu- ing pathophysiology, the rationale for treatment, and

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. doi: 10.1210/jc.2015-3910 press.endocrine.org/journal/jcem 7 signs and symptoms indicative of complications of the dis- concurrently receive calcitriol supplements. Thiazides and order. This is particularly important due to the fact that phosphate binders were not used in any of the studies. A hypoparathyroidism is a rare disorder, and medical pro- 28-week study by the same group comparing daily with viders may not be familiar with the potential manifesta- twice daily injections showed twice-daily dosing with tions of the disease. In addition, the patient who under- PTH (1–34) produced significantly higher serum calcium stands the importance of preventing kidney damage due to levels with less fluctuation throughout the day while si- excessive urinary calcium excretion might be more accept- multaneously normalizing urine calcium levels in patients ing of the 24-hour urine collections, as well as other mon- of all etiologies except those with a calcium receptor mu- itoring approaches that might otherwise be seen as an in- tation (74). A longer 3-year study by Winer et al showed convenience. Ongoing care with a provider familiar with PTH (1–34) superior to active vitamin D by maintaining the treatment of this disorder is critical for meeting the urinary calcium excretion in the normal range along with complex needs of patients and to optimize their outcomes. stable bone density Z-scores in adults and children (75). Children receiving PTH (1–34) over three years had stable Replacement therapy of hypoparathyroidism with renal function, normal linear growth and bone accrual PTH peptides (76). Hypoparathyroidism is typically managed with cal- To further refine replacement therapy with PTH (1– cium, active vitamin D, and, at times, thiazide diuretics. 34), Winer recently utilized a pump delivery system and With sufficient expertise the serum calcium can be main- compared it with twice daily injections (77, 78). In this tained, although often requiring the use of very high doses 6-month study, pump delivery produced normal, steady of calcium and active vitamin D. Some individuals, how- state calcium levels with minimal fluctuation and avoided ever, despite valiant efforts continue to be difficult to con- the rise in serum and urine calcium levels that are evident trol on conventional therapy, even when high doses are soon after PTH (1–34) injection. The marked reduction in employed. Moreover, there are concerns with prolonged urinary calcium excretion when PTH (1–34) is adminis- use of calcium and active vitamin D in large doses, par- tered by pump would appear to emphasize a physiological ticularly with regard to hypercalciuria, nephrolithiasis, point that PTH has to be continuously exposed to the renal nephrocalcinosis and ectopic soft tissue calcification (22). tubule in order for the renal calcium-conserving effects to In addition, conventional therapy with calcium and active be realized. Pump delivery of PTH (1–34) achieved simul- vitamin D does not alleviate quality of life (QOL) com- taneous normalization of markers of bone turnover, se- plaints (64, 70, 71) nor does it reverse abnormalities in rum calcium, and urine calcium excretion. These results bone remodeling characteristic of the disease (72). In were achieved with a smaller daily PTH (1–34) dose and short, conventional therapy does not provide a physiolog- a reduced need for magnesium supplementation com- ical replacement remedy for the lack of PTH in pared with the twice daily PTH (1–34) injection regimen. hypoparathyroidism. Until recently, hypoparathyroidism was the last re- Use of rh PTH (1–84) in hypoparathyroidism maining classic endocrine deficiency disease for which the The rationale for using rhPTH (1–84) for hypopara- missing hormone was not an approved therapy. Over the thyroidism is that, in contrast to PTH (1–34), it is the past two decades, studies of teriparatide [PTH (1–34)] and native hormone and, thus, would replace what is truly the full-length natural secretory product of the parathy- missing in this disease. For reasons that have not been fully roid glands, PTH (1–84), have ushered a new era in the elucidated, the effective half-life of PTH (1–84) is longer management of this disease. In January, 2015, the FDA than PTH (1–34) resulting in protocols that have been able approved the use of recombinant human (rh) PTH (1–84) to utilize effectively once daily dosing (25, 75, 76). Initial for the management of hypoparathyroidism (73). studies demonstrated proof of concept with daily or every other day dosing by showing maintenance of serum cal- Use of PTH (1–34) in hypoparathyroidism cium while significantly reducing the need for oral calcium In a series of classic studies, Winer et al evaluated vary- and vitamin D (77, 78). ing dose regimens of the biologically active amino-termi- Sikjaer et al (78) studied 62 patients who were random- nal fragment, PTH (1–34), including once-daily and ized in a double-blind protocol comparing a fixed dose of twice-daily injections in adults and children of all etiolo- rhPTH (1–84) 100 ␮g daily or placebo for 6 months. Over gies. Early studies showed PTH (1–34) achieved superior this rather short period of time, the need for active vitamin results by maintaining normal serum calcium and urinary D and calcium supplements to maintain normal calcium calcium excretion levels when compared to conventional levels fell significantly by 50% and 11%, respectively, in therapy (74). Patients who received PTH (1–34) did not the group that received drug. Following a time course in

which serum calcium was monitored after injection, 71% rhPTH (1–84) whereas none of the placebo treated pa- of patients treated with rhPTH (1–84) developed hyper- tients showed signs of intratrabecular tunneling (81). calcemia at one or more measurements during a 24-hour In addition to these biochemical and densitometric period (76). rhPTH (1–84) reduced urinary calcium exchanges with the administration of rhPTH (1–84) in hy- cretion 2–8 hours after injection but over the 24-hour poparathyroidism, changes in QOL (QoL) metrics are also period, urinary calcium excretion did not change (76). noteworthy. In the short-term study of Sikjaer et al, QoL Similarly, urinary phosphate excretion increased only dur- as assessed by the 36-item Short Form Health Survey (SF- ing the first 8 hours after rhPTH (1–84) injection (76). 36) was significantly reduced in hypoparathyroid patients In longer studies, rhPTH (1–84) replacement therapy compared with norm-based scores. Compared with pla- continued to demonstrate these advantages (79, 80). In the cebo, rhPTH (1–84) did not improve QoL (71). The work work of Cusano et al, reductions in oral calcium and vi- of Cusano et al also confirmed the reduction in QoL mea- tamin D requirements were significant and maintained sures in hypoparathyroid subjects by the SF-36 scale. In over a 4-year period along with serum calcium levels that contrast to the work of Sikjaer et al, however, the work of were maintained (79). Reductions in urinary calcium ex- Cusano et al which extended over a longer period of time cretion were more variable and not constant over time but demonstrated a significant increase in virtually all 8 QOL did achieve significance at 3 years. Bone mineral density of measures at 1 year (70). These improvements were sus- the lumbar spine by DXA increased, while hip density was tained over a period of 5 years (80). stable and the distal 1/3 radius site fell. The work of Sikjaer et al showed small but significant declines at the spine and Phase III study of rhPTH (1–84) in hip, but not the 1/3 radius, by DXA. However, in contrast hypoparathyroidism to areal BMD measurements by DXA, trabecular volu- The pivotal phase III trial of rhPTH (1–84) in hypo- metric BMD as assessed by quantitative CT (QCT) scans parathyroidism was reported by Mannstadt et al (83). at the lumbar spine actually increased significantly in re- This multicenter, multinational, placebo-controlled, dou- sponse to therapy. ble blinded trial compared rhPTH (1–84) administered Newer imaging modalities are being assessed to deter- with a titration algorithm (50 ␮g could be increased to 75 mine other aspects of rhPTH (1–84) therapy in hypopara- ␮gorto100␮g). The trial’s triple primary end point was thyroidism. Trabecular Bone Score (TBS), a textural anal- a) reduction of calcium supplementation by 50% or more; ysis of the lumbar spine DXA image, shows values that are b) reduction of active vitamin D supplementation by 50% within the normal range in patients who have not been or more; 3) maintenance of a stable serum calcium levels treated with PTH. After rhPTH (1–84) for up to 4 years, within the normal range. The results of the study showed TBS values increase in both premenopausal and post- that 53% of study subjects receiving rhPTH (1–84) met menopausal women. By QCT, Sikjaer et al (81) have this triple primary end point, while only 2% of study sub- shown that the cortical, but not the trabecular, compart- jects receiving placebo did so (P Ͻ .001). The secondary ment of the hip, is reduced with rhPTH (1–84) therapy. Bone turnover markers increase quickly and markedly endpoint, the proportion of subjects who were able to with the administration of rhPTH (1–84). Both bone for- eliminate all active vitamin D supplemtnation while re- mation and bone resorption markers reach a peak within ducing the dose of oral calcium to no more than 500 mg approximately a year and then decline to levels that rep- per day was also highly significant in favor of the study Ͻ resent a new baseline that is higher than pretreatment subjects who received rhPTH (1–84): 43% vs. 5% (P baseline values. These results are confirmed at the tissue .001). In most study subjects (52%), rhPTH (1–84) was ␮ level by histomorphometric analysis of bone biopsies from titrated up to a dose of 100 g/d. Adverse events were patients with hypoparathyroidism. As shown by Rubin et similar with the most common reports related to signs of al, transiliac crest bone biopsies using a quadruple label hypocalcemia, namely, muscle spasms, paresthesias, technique demonstrate a marked increase in tetracycline- headache and nausea. labeled surfaces, representing bone formation, within 3 Two other studies with rhPTH (1–84) have been re- months of rhPTH (1–84) administration (82). By more ported recently. RELAY is a short, 8 week, double- standard conventional bone biopsy techniques, marked blinded, multinational, randomized trial that tested changes in both trabecular and cortical compartments are whether doses as low as 25 ␮g per daily could be effica- seen. Within a year, trabecular width is reduced and tra- cious in hypoparathyroidism (84, 85). Although some becular number is increased. In the work of Sikjaer et al, study subjects were able to meet the primary end point intratrabecular tunneling could be demonstrated in ap- (oral calcium not more than 500 mg/d and active vitamin proximately half of the biopsied subjects treated with D not more than 0.25 ␮g/d) most patients did not, con-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. doi: 10.1210/jc.2015-3910 press.endocrine.org/journal/jcem 9 firming the results of the REPLACE trial that most patients subcutaneous injection into the thigh and to concomi- require amount of rhPTH (1–84) more than 50 ␮g/d. tantly decrease the dose of active vitamin D by 50%. Se- The other study of recent note is called RACE. This trial rum calcium (and albumin) concentrations are to be mon- is an open-label, extension of the REPLACE and RELAY itored every 3–7 days after initiation of therapy and after trials conducted in the United States only (84–86). The each dose change. The dose of rhPTH (1–84) is to be initial results at 1 year provide confirmatory evidence of titrated every four weeks with the goal to discontinue ac- the primary end points of the REPLACE trial, carried out tive vitamin D and to reduce oral calcium supplements to for 1 year. an amount as low as 500 mg per day while keeping serum calcium within the low-normal range. As an alternative to Management guidelines the recommended reduction of active vitamin D first (as With the recent approval of rhPTH (1–84) by the U.S. was done in the REPLACE trial), reducing oral calcium Food and Drug Administration (FDA), replacement ther- first (also by 50%), especially if the calcium supplement apy is now available and is expected to contribute to im- use is high, should also be possible. The final dosage re- proved management of hypoparathyroidism. Approved as quirement of rhPTH (1–84) required for each patient to an adjunct to calcium and vitamin D, rhPTH (1–84) is achieve optimized management cannot be predicted by recommended for patients who cannot be well-controlled parameters such as weight or previous amounts of calcium on conventional therapy alone. This directive leaves room and active vitamin D via conventional treatment. After the for interpretation of what constitutes a well-controlled initial titration phase when a stable regimen is achieved, individual. The physician should consider the following serum calcium and phosphate should be monitored every questions when assessing whether the patient is or is not 3–6 months and urinary calcium excretion at least yearly. well controlled. It is possible that some patients who have been started 1. Does the patient’s serum calcium exhibit large swings on rhPTH (1–84) will be advised or, on their own, decide with frequent episodes of significant hypo- and/or to stop therapy. Prior to discontinuing rhPTH (1–84), hypercalcemia? serum 25-hydroxyvitamin D levels should be in the nor- 2. Can the serum phosphate and/or calcium-phosphate mal range. For patients receiving rhPTH (1–84) alone product be maintained within acceptable range? without any calcium and vitamin D analogs, a brief period 3. Is the risk for renal complications high due to hy- of therapy with concomitant rhPTH (1–84), calcitriol, er- percalciuria or an unfavorable urinary biochemical stone go- or cholecalciferol (parent vitamin D) and calcium may risk profile despite optimization of conventional therapy? be necessary to allow the usual 3–4 day onset of conven- 4. Does the patient show evidence for renal complica- tional therapy to become fully effective. Furthermore, be- tions such as nephrocalcinosis, nephrolithiasis, or chronic fore discontinuing chronic rhPTH (1–84) therapy, one renal kidney disease? should consider potential factors that may lead to a height- 5. Is the amount of oral medications required to control ened risk for sudden hypocalcemia such as malabsorption, symptoms of hypocalcemia excessive? illness, and menses in premenopausal women. A recent 6. Does the patient have a condition that might render case series described acute hypocalcemia in two patients calcium and vitamin D absorption from the GI tract vari- after the abrupt discontinuation of chronic PTH (1–34) able (eg, malabsorption, inflammatory bowel disease, or therapy. To avoid this, subsequent patients received two- celiac disease)? to threefold the baseline requirements of standard therapy 7. Does the patient have an autosomal dominant form during their transition from PTH (1–34) (87). of hypocalcemia due to an activating mutation in the calcium sensing receptor? These patients are at great risk of Safety renal damage. Similar to rhPTH (1–34) for the treatment of osteopo- The decision to recommend the use of rhPTH (1–84) in rosis, rhPTH (1–84) was approved by the FDA with a hypoparathyroidism should also take into account the fact ‘black box’ warning due to the evidence that both PTH that it is at this time a very expensive therapy. The points molecules cause osteosarcoma in rats (88, 89). Approval made above with regard to considering rhPTH (1–84) as of teriparatide for osteoporosis is limited to 2 years at a 20 a therapy for hypoparathyroidism, should, therefore, also ␮g daily dose but no limit has been imposed on the dura- bear in mind cost of the product. tion of rhPTH (1–84) therapy for hypoparathyroidism. With extensive clinical human experience with PTH (1– An approach to management with rhPTH (1–84) 34) since its approval 13 years ago and with rhPTH (1–84) The official recommendations are stated in the package for a shorter period of time, no signals with either peptide insert to initiate rhPTH (1–84) at 50 ␮g once daily as a have emerged to suggest that human subjects treated with

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 March 2016. at 08:01 For personal use only. No other uses without permission. . All rights reserved. 10 Management of Hypoparathyroidism J Clin Endocrinol Metab either form of PTH are at increased risk for the develop- No other co-authors report any conflicts of interest. ment of osteosarcoma (90–92). Only a handful of cases of This work was supported by . osteosarcoma have appeared in human subjects exposed to teriparatide, a number that is below what would be expected on the basis of epidemiological considerations of References the background incidence of osteosarcoma in human sub- 1. Rizzoli R, Bonjour JP. Physiology of calcium and phosphate ho- jects (92). In the ongoing surveillance registry of osteo- meostasis. In: Seibel MJ, Robins SP, Bilezikian JP, eds. Dynamics of sarcoma, there is no evidence that any subject with osteo- bone and cartilage metabolism. 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Am J Physiol. 1983;244:E313–316. 14. Smith BJ, Bu SY, Wang Y, Rendina E, Lim YF, Marlow D, Clarke SL, Cullen DM, Lucas EA. A comparative study of the bone meta- Acknowledgments bolic response to dried plum supplementation and PTH treatment in adult, osteopenic ovariectomized rat. Bone. 2014;58:151–159. Address all correspondence and requests for reprints to: Corre- 15. Zhang J, Lazarenko OP, Blackburn ML, Shankar K, Badger TM, sponding author: John P. Bilezikian, Columbia University Col- Ronis MJ, Chen JR. Feeding blueberry diets in early life prevent senescence of osteoblasts and bone loss in ovariectomized adult fe- lege of Physicians, Surgeons, Department of Medicine, 630 West th male rats. PLoS One. 2011;6:e24486. 168 Street, PH 8W-864, NY, NY 10032, Phone: (212) 342– 16. Bonnet N, Somm E, Rosen CJ. Diet and gene interactions influence 5383, Fax: (212) 305–6486, Email: [email protected]. the skeletal response to polyunsaturated fatty acids. Bone. 2014; Report #4 from the First International Conference on “The 68:100–107. Diagnosis, Management and Treatment of Hypoparathyroid- 17. Hie M, Tsukamoto I. Administration of zinc inhibits osteoclasto- ism” held in Florence, Italy May 7–9, 2015 genesis through the suppression of RANK expression in bone. Eur Disclosure statements: Dr. Bilezikian is a consultant for Am- J Pharmacol. 2011;668:140–146. gen, Eli Lilly, Radius, and Merck and receives research support 18. Hohman EE, Weaver CM. A grape-enriched diet increases bone from Shire Pharmaceuticals. Dr. Rubin receives research support calcium retention and cortical bone properties in ovariectomized from Shire Pharmaceuticals. Dr. Brandi is a consultant for Alex- rats. J Nutr. 2015;145:253–259. 19. Atkinson C, Compston JE, Day NE, Dowsett M, Bingham SA. The ion, Abiogen, Amgen, Bruno Farmaceutici, Eli Lilly, Merck, effects of phytoestrogen isoflavones on bone density in women: a Shire Pharmaceuticals, SPA and Servier and receives research double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. support from Shire Pharmaceuticals, Amgen, Eli Lilly, and 2004;79:326–333. Merck. Dr. Potts is a founder and consultant for Radius, a con- 20. Schafer AL, Shoback D. Hypocalcemia: Definition, etiology, patho- sultant for Merck and receives research support from Chugai. genesis, diagnosis, and management. In: Rosen CJ, ed. Primer on the

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